2-(2-arylhydrazino)-2-imidazolines

ABSTRACT

COMPOUNDS OF THE FORMULA   AR-N(-R)-N(-R0)-IM   AR=ARYL RADICAL R=HYDROCARBON RADICAL OF ALIPHATIC CHARCTER IM=OPTIONALLY SUBSTITUTED 2-IMIDAZOLIN-2-YL RADICAL RO=HYDROGEN OR HYDROCARON RADICAL OF ALIPHATIC CHARACTER FOR EXAMPLE: 2-(N2-METHYL-N2-PHENYLHYDRAZINO)2-IMIDAZOLINE AND ITS SALTS. USE: ANTIHYPERTENSIVES AND VASOCONSTRICTORS.

United States Patent 3,632,602 2-(Z-ARYLHYDRAZINO)-2-IMIDAZOLINES MaxWilhelm, Allschwil, Switzerland, assignor to Ciba Corporation, New York,N.Y.

No Drawing. Filed Sept. 19, 1967, Ser. No. 668,959 Claims priority,application Switzerland, Sept. 23, 1966, 13,739/66; Aug. 16, 1967,11,488/67 Int. Cl. C07d 49/34 US. Cl. 260309.6

ABSTRACT OF THE DISCLOSURE Compounds of the formula Claims Ar=arylradical R=hydrocarbon radical of aliphatic character Im=optionallysubstituted Z-imidazolin-Z-yl radical R =hydrogen or hydrocarbon radicalof aliphatic character for example: '2-(N -methyl-N -phenylhydrazino)-Z-imidazoline and its salts.

Use: antihypertensives and vasoconstrictors SUMMARY OF THE INVENTIONDESCRIPTION OF THE PREFERRED EMBODIMENTS The aryl radicals in the newcompounds are mainly aryl radicals having at most two nuclei, forexample, naphthyl radicals or especially phenyl radicals. They may beunsubstituted or carry one, two or more identical or differentsubstituents, the said substituents being principally alkyl, alkenyl,alkoxy and alkenyloxy groups, halogen atoms and trifluoromethyl groups.

The above-mentioned alkyl groups and those mentioned hereinafter areprincipally lower alkyl groups, for example, methyl, ethyl, norisopropyl groups or the various isomers butyl or pentyl groups. Alkenylgroups are especially lower alkenyl groups, for example, allyl groups;the alkoxy groups are, in particular, lower alkoxy groups, for example,methoxy or ethoxy groups or the various isomeric propoxy, butoxy orpentoxy groups. Alkenyloxy groups are especially lower alkenyloxygroups, for example, allyloxy groups; halogen atoms are primarilyfluorine, chlorine or bromine atoms.

A hydrocarbon radical having aliphatic characteristics and which may besubstituted, represented by R, is, for example, an aliphatic,cycloaliphatic or araliphatic hydrocarbon radical, for example,especially an alkyl or alkenyl radical, a cycloalkyl, cycloalkenyl orcycloalkylalkyl radical which may be substituted by alkyl radicals or aphenylalkyl radical which may be substituted in the phenyl ring, asindicated above.

Cycloalkyl and cycloalkenyl radicals are, for example,

cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl orcyclohexenyl radicals.

3,632,602 Patented Jan. 4, 1972 .Substituents of the hydrocarbonradicals having aliphatic characteristics R are, for example, hydroxylgroups or alkoxy groups, for example, those mentioned above.

The new compounds may be further substituted, for example, at the carbonatoms of the imidazolinyl radical by alkyl radicals, or at the secondarynitrogen atoms of the hydrazino group and the imidazolinyl radical byhydrocarbon radicals having aliphatic characteristics which may besubstituted. The said radicals are those mentioned above.

The new compounds possess valuable pharmacological properties. Forexample, tests carried out on renalhypertensive rats show them, inparticular, to have antihypertensive activity. Furthermore, testscarried out on isolated vessels from the hind extremities of rabbitsshow that they act as vasocontrictors. Thus, the new compounds can beused pharmacologically on animals or in medicament form asantihypertensives or local vasoconstrictors. The new compounds are alsovaluable intermediate products suitable for use in the preparation ofother useful substances, especially pharmacologically useful compounds.They are also suitable as piloerective agents.

Compounds which are specially valuable in respect of theirpharmacological properties are those of the formula Ice in which Phrepresents a phenyl radical which may be substituted, for example, inthe manner indicated above and R represents a lower alkyl radical, andespecially Z-N -methyl-N -phenylhydrazino)-Z-imidaxoline of the formulawhich, for example, has a pronounced hypotensive action onrenalhypertensive rats when administered orally in repeated doses of 0.1to 1.0 mg./kg./day.

The new compounds can be manufactured by known methods, for example, bycondensing a salt of an S-lower alkyl isothiosemicarbazide whichcontains an aryl radical and the above-mentioned radical R in l-positionwith a corresponding ethylenediamine which does not contain more thanone substituent at its nitrogen atoms.

The reaction is carried out in the usual manner, advantageously in thepresence of diluents, such as lower alkanols, if desired or required, inthe presence of condensing agents, at room temperature or at an elevatedtemperature.

Depending on the conditions under which the process is carried out andon the kind of starting materials used, the end product is obtained inthe free state or in the form of the acid addition salts thereof, whichare like wise included in the invention. For example, basic, neutral ormixed salts can be obtained, and, if necessary, hemi-, m0no-, sesquiorpolyhydrates thereof. The acid addition salts of the new compounds canbe converted in known manner into the free compound, for example, bymeans of basic agents, for example, alkalis or ion exchangers. The freebase obtained can form salts with organic or inorganic acids. The acidsused in the preparation of acid addition salts are, in particular,therapeutically useful acids, for example, hydrohalic acid, sulfuricacid, phosphoric acids, nitric acid, perchloric acid; aliphatic,alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, forexample, formic acid, acetic acid, propionic acid, succinic acid,glycolic acid, lactic acid, malic acid, tartaric acid, citric acid,ascorbic acid, maleic acid, bydroxymaleic acid or pyruvic acid;phenylacetic acid,

benzoic acid, para-amino-benzoic acid, anthranilic acid,para-hydroxy-benzoic acid, salicyclic acid or para-aminosalicyclic acid,methylene-bis-(Z-hydroxynaphthoic acid- 3), methanesulfonic acid,ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid;halogen-benzenesulfonic acid, toluenesulfonic acid, naphthalene sulfonicacid; methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, for example, picrates, canalso be used in the purification of the free compounds obtained in thatthe free compound is converted into salts, the salts are separated andthe free compound is liberated from the salts.

In view of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a free base is referredto in this context, a corresponding salt is also intended, provided suchas possible or appropriate under the circumstances.

The invention also relates to any modification of the process in whichan intermediate product obtainable at any stage thereof is used asstarting material and any remaining steps are carried out, or theprocess is discontinued at any stage thereof, or in which a startingmaterial is formed under the reaction conditions, or in which a reactantmay be used in the form of their salts.

Those compounds which are not mentioned in the literature can be made byknown methods.

In the reactions of the invention, the starting materials chosen arepreferably those which yield the compounds described above as being thepreferred compounds.

The new compounds may be used, for example, in the form ofpharmaceutical compositions which contain them in free form or in theform of a physiologically tolerable salt in admixture or conjunctionwith an organic or inorganic, solid or liquid pharmaceutical excipientsuitable for enteral, parenteral or local administration. The saidexcipient must not react with the new compounds, suitable substancesbeing, for example, water, gelatine, lactose, starch, colloidal silica,magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums,polyalkylene glycols, cholesterol or other known pharmaceuticalexcipients. The pharmaceutical preparations may be in the form oftablets, coated tablets, pills, capsules, suppositories, salves, creams,or in the form of solutions (e.g. as elixers or syrups), suspensions oremulsions. If necessary, they may be sterilized and/ or containadjuvants, for example, preservatives, stabilizing agents, wettingagents or emulsifying agents, salts for regulating osmotic pressure orbuffers. They may also contain other therapeutically useful substances.The pharmaceutical preparations are made by known methods. In the sameway, the new compounds may be presented in the forms generally used inthe application of piloerectors, e.g. as lotions.

The following examples illustrate the invention.

Example 1 30.0 grams of N -phenyl-N-rnethyl-S-methyl-isothiosemicarbazide-hydroiodide are boiled for 4hours under reflux in 100 ml. of ethanol together with 15 grams ofethylenediamine. The batch is evaporated in a water-jet vacuum, theresidue is dissolved in 2 N sodium hydroxide solution and the solutionis filtered. The filtrate is rendered alkaline by the addition of 10 Nsodium hydroxide solution and is subsequently extracted with methylenechloride. After drying and evaporation of the solvent, an oil remainswhich is dissolved in ml. of absolute ethanol; 5 ml. of 10 Nhydrochloric acid in ethanol are then added. Crystallization occursafter the addition of ether. 2-(N methyl N phenyl hydrazino) 2imidazoline hydrochloride of the formula is obtained in the form ofcrystals which melt at 198 to 199 C. subsequent to recrystallizationfrom isopropanol.

The N phenyl N methyl S methyl isothiosemicarbazide used as startingmaterial can be obtained in the following manner:

32 grams of benzoylisothiocyanate are added dropwise to a solution of 22grams of N-methyl-N-phenylhydrazine in 300 ml. of methylene chloride.The batch is then heated for 3 hours at 50 C. while stirring. Thesolution is then evaporated to half its volume, petroleum ether is addedand the precipitate which is salted out is isolated by filtration. Theproduct obtained in N -phenyl-N -methyl-N benzoyl-thiosemicarbazidemelting at 138 to 140 C.

28.5 grams of N -phenyl-N -methyl-N -benzoyl-thiosemicarbazide areheated for 30 minutes at C. with 200 ml. of 10% sodium hydroxidesolution while stirring. The portion which precipitates is isolated byfiltration and crystallized from methanol. The product obtained is Npheny1-N methyl-thiosemicarbazide in the form of crystals melting at 188to 189 C.

18.1 grams of N -phenyl-N -methyl-thiosemicarbazide are stirred for 5hours at 50 C. in ml. of ethanol together with 15.0 grams of methyliodide. The solution is then evaporated and the residue isrecrystallized from ethanol/ether. The product obtained is N -pheny1-Nmethyl-S-methyl-isothiosemicarbazide in the form of crys tals melting at136 to 138 C.

Example 2 A solution containing 2-(N -phenyl-N-methylhydrazino)-2-imidazoline hydrochloride can be prepared, forexample from the following ingredients:

0.10 g. of 2-(N -phenyl-N -methylhydrazino)-2-imidazoline hydrochloride0.28 g. of primary sodium phosphate 0.30 g. of secondary sodiumphosphate 0.70 g. of sodium chloride 0.01 g. of benzalkonium chloridewater to make up 100 ml.

The solution is suitable, application.

for example, for nasal Example 3 Tablets each containing 0.05 g. of 2-(N-phenyl-N methyl-hydrazino)-2-imidazoline hydrochloride can be prepared,for example from the following ingredients:

Per tablet (mg) 2 (N -phenyl-N -methylhydrazino) -2-imidazolinePreparation.-The 2- N -phenybN -methylhydrazi no Z-imidazolinehydrochloride is mixed with part of the wheat starch, with the lactoseand the colloidal silicic acid, and the mixture forced through a sieve.In a water bath, the remainder of the wheat starch is pasted with 5times its quantity of Water and the powder mixture kneaded with theresulting paste until a slightly plastic mass is obtained. This mass isforced through a sieve having a mesh width of 3 mm., dried, and the drygranulate also forced through a sieve. After that, the arrowroot, thetalc and the magnesium stearate are admixed and the resulting mixturecompressed into tablets each weighing 100 mg.

Example 4 In an analogous manner to that described in Example 1,

there may be prepared 2- [2- (para-methoxyphenyl) -2-ethylhydrazino]-1-methy1-2- imidazoline,

2-[Z-(meta-allylphenyl)-2-cyclopentyl-hydrazino]-4-methyl-Z-imidazoline,

2- [2-(ortho-chlorophenyl) -2-benzyl-1-methylhydrazino] Z-imidazoline,

2- [2- (para-trifiuoromethylphenyl) -2phenethylhydrazino]4-ethyl-2-imidazo1ine,

2- 2- (para-tolyl -2- (para-methoxybenzyl) -hydrazino]4,5-dimethyl-2-imidazoline and 2- 2- (allyloxyphenyl) -2-(meta-chlorobenzyl) -hydrazino] 4,4-dimethyl-2-imidazoline and theirhydrochlorides.

I claim: 1. A member selected from the group consisting of compounds ofthe formula in which R and R each stands for a member selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, lower alkoxy,lower alkenyloxy, halogen and trifluorornethyl, R for a member selectedfrom the group consisting of lower alkyl, cyclo-lower alkyl,phenyl-lower alkyl and phenyl-lower alkyl substituted by a memberselected from the group consisting of lower alkyl, lower alkenyl, loweralkoxy, lower alkenyloxy, halogen and trifluoromethyl, R and R eachstands for a member selected from the group consisting of hydrogen andlower alkyl, and R R R and R each stands for a member selected from thegroup consisting of hydrogen and lower alkyl, and their acid additionsalts.

2. A product as claimed in claim 1, in which R stands for lower alkyl, RR R and R each stands for hydrogen.

3. A product as claimed in claim 1, in which -R stands for lower alkyland R R R R R and R each stands for hydrogen.

4. A product as claimed in claim 1, in which R stands for lower alkyland R R R R R R R and R each stands for hydrogen.

5. A product as claimed in claim 1, which product is the2-(Z-methyl-2-phenyl-hydrazino)-2-imidazoline or an acid addition saltthereof.

References Cited UNITED STATES PATENTS 2,868,802 1/1959 Hueni 260'309.62,915,431 12/1959 Carron et al. 260309.6 2,93 8,038 5/1960 Hirt 260309.63,190,802 6/1965 Zeile et a1 260309.6 3,288,805 11/1966 Berg 260-30963,300,511 1/1967 Zeile et a1 260309.6 3,480,630 11/1969 Stahle et al260309.6

OTHER REFERENCES Burger: Medicinal Chemistry, 2nd ed., pp. 607-8, N.Y.,Interscience, 1960, RS 403.B8.

Bontempo et al.: Finland et al., Antimicrobial Agents and Chemotherapy,1961, pp. 795-l.

Detroit, Amer. Soc. Microbiology, 1962, RS 161.A59.

Usui et al.: Jour. Pharm. Soc. (Japan), vol. 87, pp. 51, 58 and 64relied on (January 1967) RS 1.P45.

Adcock et al.: Jour. Chem. Soc. (London), 1965, p. 478 relied on(January 1965).

NATALIE TROUSOF, Primary Examiner US. Cl. X.R. 424273

